H₂O₂ responsive CO gas release platform with CA IX-Targeting for inhibiting tumor growth and metastasis

Carbon monoxide (CO) gas therapy has emerged as a highly promising anti-tumor strategy. However, targeting delivery and controlled intratumoral release of CO still have unsatisfactory outcomes. Herein, we constructed a novel CO therapeutic platform consisting of a carbonic anhydrase IX (CA IX) inhibitor (CAI) and intelligent responsive CO-releasing molecules (CORMs). The formed platform coupled with CAI can actively target CA IX overexpressed tumor cells to achieve targeted delivery of CORMs. After reaching the tumor site and being internalized by tumor cells, CORMs can be activated by the endogenous H₂O₂, realizing the light induced excited-state intramolecular proton transfer (ESIPT) effect and spatiotemporal controllable release of CO. Next, CAI can prevent tumor metastasis by inhibiting CA IX to alleviate the acidic tumor extracellular environment, while the generated CO can also achieve tumor metastasis inhibition by inhibiting vascular endothelial growth factor (VEGF). In vitro and in vivo experiments indicate that the constructed CO gas therapeutic platform can significantly inhibit tumor growth and metastasis, which provides a new direction for tumor gas therapy.